Gold catalysis: Regio- and stereoselective total synthesis of xyloketals D and G and the related natural product alboatrin

Article abstract of DOI:10.1021/jo302545n

A new and efficient one-pot desilylation-gold-catalyzed cycloisomerization of alkynes containing a silyl-protected phenolic -OH and a free alcoholic -OH unit leads selectively to the formation of tetrahydrofuranobenzopyran ring system. This approach has been used for the regio- and stereoselective synthesis of xyloketal D, xyloketal G, and the related natural product alboatrin.

Full text of DOI:10.1021/jo302545n

Article
pubs.acs.org/joc
Gold Catalysis: Regio- and Stereoselective Total Synthesis of
Xyloketals D and G and the Related Natural Product Alboatrin
Biswajit Panda and Tarun K. Sarkar*
Department of Chemistry, Indian Institute of Technology, Kharagpur-721302, India
S
* Supporting Information
ABSTRACT: A new and efficient one-pot desilylation−gold-
catalyzed cycloisomerization of alkynes containing a silyl-protected
phenolic −OH and a free alcoholic −OH unit leads selectively to the
formation of tetrahydrofuranobenzopyran ring system. This approach
has been used for the regio- and stereoselective synthesis of xyloketal
D, xyloketal G, and the related natural product alboatrin.
Recently, homogeneous catalysis using gold salts has
emerged as one of the most dynamic fields in organic
synthesis.7 On the basis of their ability to activate C−C triple
bonds as soft, carbophilic Lewis acids, gold salts are ideally
suited for the formation of C−C and C−heteroatom bonds by
nucleophilic attack to these activated substrates. One of the
areas where gold has registered its supremacy over other
transition metals is the catalytic cycloisomerization of
alkynediols,8 and this has emerged as an efficient strategy to
build complex ketal systems in just one step.9 In continuation
of our work on gold-catalyzed organic transformations,10 we
report herein a novel gold-catalyzed cycloisomerization strategy
for the synthesis of xyloketal natural products, e.g., xyloketal D
(2), xyloketal G (3), and the related natural product alboatrin
(4).
INTRODUCTION
■
Xyloketals, originated from the mangrove fungus sp. (no.
2508), are a family of novel ketal compounds having a close
biogenetic relationship.1 The unique characteristics of this
series of molecules is the cis disposition of three contiguous
stereogenic centers embedded in the tetrahydrofuranobenzo-
pyran moiety (Figure 1). Among them, xyloketal A (1) is most
RESULTS AND DISCUSSION
■
At the outset, our focus was on the linear tricyclic
tetrahydrofuranobenzopyran ring system 9 (Scheme 1) as
enshrined in xyloketals and the related natural product,
alboatrin (4). We thought a triple bond could be used as the
oxidation-state equivalent to a ketone as has been documented
in a number of recent publications.11 Thus, the required
Figure 1. Structures of xyloketals A (1), D (2), and G (3) and
alboatrin (4).
Scheme 1. Retrosynthetic Pathway for the Compound 9
notable in view of its remarkable C3 symmetry. Xyloketal D (2)
and its regioisomer, xyloketal G (3),2 represent simpler
structural analogues of 1. Both xyloketal A (1) and D (2) are
known to inhibit acetylcholine esterase3 and are considered
potential lead compounds for the treatment of neurological
disorders like Alzheimer’s disease. Incidentally, a structurally
related natural product alboatrin (4), isolated from the fungus
Verticillium albo-atrum,4 also shows significant biological activity
in that it inhibits the root growth of the host plant (Maris
Kabul) and causes vascular-wilt disease in alfalfa.5 Over the
years, the structural novelty and associated biological properties
of xyloketals and alboatrin have triggered intense interest within
the synthetic community.6,15
Received: November 29, 2012
Published: February 21, 2013
© 2013 American Chemical Society
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Scheme 2. Synthesis of Model Compound 9
pendant alkyne 8 on activation by a gold catalyst may allow
addition of two hydroxyl groups (an alcoholic −OH and a
phenolic −OH) to the alkyne so as to form compound 9.
Because this cycloisomerization (8 → 9) is reversible, one
would expect it to provide the thermodynamically more stable
product having a cis ring junction. Compound 8 may be
available from deprotection of protected phenol 7. The alkyne
7 could be made via a DIBAL-H reduction of 6 to the
corresponding lactol (not shown) followed by alkynylation.
The lactone 6 is obtainable by alkylation of γ-butyrolactone
with substituted benzyl bromide 5.
The synthesis commenced with the known silyl-protected 2-
hydroxybenzyl bromide 10.12 Thus, alkylation of γ-butyrolac-
tone with 10 gave lactone 11 in 82% yield (Scheme 2). DIBAL-
H reduction of 11 to lactol (not shown) followed by TMS-
diazomethane-mediated alkynylation (Colvin rearrangement)13
gave the alkyne 12 in 78% overall yield.14 Deprotection of silyl
group by TBAF gave phenol 8 in 98% yield. To test the gold-
catalyzed cycloisomerization, AuCl (3 mol %) was added to a
methanol solution of 8 at room temperature; after 2 h of
stirring, it gave the tricyclic ketal 915 incorporating the basic
structural framework of the xyloketals in 81% isolated yield.
Although metal-catalyzed spiroketalization of alkynes with
alcohols are known in the literature,8,9 this type of linear cyclic
ketal formation namely, xyloketalization is uncovered for the
first time. Note that the gold-catalyzed xyloketalization is highly
stereoselective and furnished only the cis-diastereomer
unaccompanied by even traces of trans-diastereomer. Fur-
thermore, addition of a catalytic amount of PPTS increases the
reaction rate such that the reaction was completed within 30
min with excellent yield (96%).
At this stage it occurred to us that isolation of 8 (Scheme 2)
is avoidable and that conversion of 12 to 9 could be carried out
as a one-pot reaction. Indeed, the literature is replete with cases
where the gold−fluoride compatibility has been documented.16
However, many authors continue to follow two-step strategies,
first desilylation and then gold-catalyzed reaction, en route to
their targets.17 In the event, we added a methanol solution of
alkyne 12 to a methanol solution of AuCl (3 mol %), TBAF
(1.1 equiv), and PPTS (1.2 equiv) as proton source; after 1 h of
stirring at room temperature the reaction yielded the tricyclic
ketal 9 in 96% isolated yield.
Further experimentation (Table 1) showed that AuCl and
AuCl3 (entries 1 and 9) are the catalysts of choice in presence
of fluoride ion for this reaction. Absence of TBAF (entry 2),
however, resulted in complete decomposition of the starting
material, although absence of a proton source, e.g., PPTS (entry
3) does yield traces of product (TLC). When HgCl2, FeCl3, and
Table 1. Xyloketalization of 12 under Various Catalytic
a
Systems
b
entry
catalyst
time (h)
yield (%)
c
1
2
3
4
5
6
7
8
9
AuCl
1
12
12
6
96
d
AuCl
0
e
AuCl
traces
HgCl2
FeCl3
CuCl2
AgOTf
PtCl2
AuCl3
0
6
0
6
0
5
11
44
92
2
1
f
10
12
0
a
All of the reactions were performed using 12 (0.2 mmol), TBAF
(0.22 mmol), and PPTS (0.24 mmol) in the presence of catalyst (3
mol %) in methanol (6 mL) at room temperature or as otherwise
b
c
noted. Isolated yield. Isolated yield in toluene (11%), CH2Cl2
(42%), and THF (80%). In the absence of TBAF. In the absence
of PPTS. In the absence of catalyst.
d
e
f
CuCl2 were used (entries 4−6), no traces of the desired
product could be observed in the crude reaction mixtures by
TLC analysis; only decomposition of starting material resulted.
Other carbophilic Lewis acids such as AgOTf and PtCl2 gave
the desired product, albeit in lower yields (entries 7 and 8). In
the absence of catalyst, this reaction yielded only the desilylated
product 8 in excellent yield (entry 10). Other solvents, e.g.,
toluene, CH2Cl2, and THF, proved to be less efficient in this
reaction (entry 1, Table 1) as under these conditions the
desired product was obtained in 11%, 42%, and 80% yields,
respectively.
With the verified success of our approach to the xyloketal
core through a synthesis of the simple model compound, we
decided to first apply the methodology to a synthesis of
noralboatrin (13). We began our synthesis with the silyl-
protected orcinol 2-carboxaldehyde 1418 (Scheme 3). Aldol
condensation of 14 with γ-butyrolactone resulted in a complex
mixture, probably resulting from further reactions of the
initially formed aldol product including scrambling of the silyl
groups. This problem was readily overcome when the aldol
condensation was carried out with the known aldehyde 15
containing −OMe groups instead of −OTBS groups, thereby
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Scheme 3. Synthesis of Noralboatrin (13)
Scheme 4. Synthesis of Alboatrin (4)
providing 16 in 91% isolated yield as a single diastereomer; we
made no attempt to determine its stereochemistry as it is
irrelevant for the synthesis. Reduction of 16 with Et3SiH in
presence of boron trifluoride diethyl etherate afforded
compound 17 in excellent yield. Demethylation of 17 gave a
dihydroxy compound which, without purification, was
protected with TBSCl by the usual way to give 18 in 78%
overall yield. With 18 in hand, we then transformed it to 19 via
DIBAL-H reduction to the corresponding lactol followed by
TMS-diazomethane mediated alkynylation. Following our
xyloketalization procedure, a methanol solution of alkyne 19
was added to a methanol solution of AuCl (3 mol %) and
TBAF (2.1 equiv) in the presence of PPTS (2.2 equiv) and the
mixture stirred for 2 h at room temperature: however, no
desired product that is 13 could be obtained. Repeated efforts
gave the same results. Incidentally, we discovered some shiny
gold metal particles settling down in the reaction vessel, which
instantly indicated that Au(I) was getting reduced to
catalytically inactive Au(0) metal particles. Since Au(I) has a
low reduction potential, it probably got reduced to Au(0) by a
highly electron-rich substrate 19 or its desilylated product.
To overcome this problem, we decided to make use of a gold
salt having comparatively high reduction potential, e.g., AuCl3
instead of AuCl. Accordingly, treatment of a methanolic
solution of 19 to a methanol solution of AuCl3 (3 mol %)
and TBAF (2.1 equiv) in presence of PPTS (2.2 equiv)
afforded noralboatrin (13)19 in 93% isolated yield.
was subjected to aldol condensation with aldehyde 15 to give
the β-hydroxy lactone 21 as a white solid in 89% isolated yield
(Scheme 4). Interestingly, the aldol reaction is highly
stereoselective and we obtained only one diastereomer; its
stereochemistry was confirmed by a single-crystal X-ray analysis
(CCDC 855274, see the Supporting Information). Reduction
of 21 with Et3SiH in the presence of boron trifluoride diethyl
etherate afforded 22 in excellent yield, which was then
transformed to 23 following the same procedure as described
in the case of noralboatrin (13). The Colvin rearrangement of
the lactol (not shown) obtained from 23 to 24 under a variety
of conditions (stirring at low temperature, e.g., −78 °C for 12−
18 h, and slowly warming to room temperature or carrying out
the reactions at room temperature overnight) proved to be
unfruitful, with the starting material being returned in each case
in moderate yield. We ascribe this failure to a possible Thorpe−
Ingold-type effect of the methyl substituent in the lactol,
thereby preventing its ring-opening and generating enough of
the free aldehyde in solution. However, heating the reaction
mixture under reflux for 3 h and using excess reagents afforded
the alkyne derivative 24 in 72% yield as a thick colorless liquid.
Using our xyloketalization procedure, addition of a methanol
solution of alkyne 24 to a methanol solution of AuCl3 (3 mol
%) and TBAF (2.1 equiv) in presence of PPTS (2.2 equiv)
furnished alboatrin (4) in 92% yield. The melting point and
spectral features (1H and 13C NMR) of our synthetic material
are identical with those reported in the literature.6f,19 This is a
facile synthesis of racemic alboatrin with 45% overall yield using
a seven-step procedure.
Our next goal was the synthesis of the natural product
alboatrin (4). In this context the racemic γ-butyrolactone 20,20
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Scheme 5. Synthesis of Xyloketal D (2) and Xyloketal G (3)
The successful synthesis of noralboatrin (13) and alboatrin
(4) propelled us to apply the same strategy to the synthesis of
xyloketals D (2) and G (3). Xyloketals D (2) and G (3) are
regioisomers. For their synthesis, we started our journey from
the known aromatic aldehydes 25 and 26 (Scheme 5). Unlike
in the case of alboatrin (4), aldol reactions of 25 and 26 were
not completely stereoselective. Thus, while each of the
carbinols 27 and 28 was formed in high yield with trans
stereochemistry of the two side chains of the lactone ring, there
was no stereocontrol in the formation of the remaining
stereocenter. This was of course of no concern as reduction of
27 and 28 yielded compounds 29 and 30 as single
diastereomers. Demethylation followed by silyl protection
furnished 31 and 32, which were then transformed into 33
and 34, the ultimate precursors for xyloketalization. Xyloketal-
ization of 33 and 34 then took place smoothly under the
previously mentioned conditions described for noralboatrin
(13) or alboatrin (4) to 35 and 36 in near-quantitative yields.
TiCl4-mediated selective acylation of 35 afforded our target
molecule rac-xyloketal D (2)6b as white solid in 82% yield. The
melting point and spectral features (1H and 13C NMR) of this
synthetic material were identical with those reported in the
literature.6b On the other hand, 36 was converted to the methyl
ether 37 (86%), a precursor in an earlier synthesis of rac-
xyloketal G (3).6i Thus, we have achieved a formal total
synthesis of rac-xyloketal G (3) as well.
Scheme 6. Proposed Mechanism for the Gold-Catalyzed
Xyloketalization
deauration furnishes the enol ether C (along with regeneration
of gold catalyst), which leads to oxonium ion D. Subsequent
nucleophilic attack of phenolic OH group furnishes the tricyclic
ketal 9. Here, PPTS plays two roles. In the first place, it acts as
proton source to yield 8 from the corresponding phenolate.
Second, it also promotes proto-deauration followed by
oxonium ion formation for the conversion of B to D.
A plausible mechanism for the gold-catalyzed xyloketalyza-
tion is shown in Scheme 6. TBAF deprotects the phenol silyl
ether of compound 12 to phenoxide which receives the proton
from PPTS to give compound 8. Then the cycloisomerization
reaction may be initiated by the formation of the alkynyl
complex A via the complexation of triple bond of 8 to the Au
catalyst. The coordination of the triple bond enhances the
electrophilicity of the alkyne as advocated for metal-catalyzed
reactions of alkynes. The addition of alcohol (5-exo-dig) may
then occur, giving the vinyl gold intermediate B. Now proto-
CONCLUSION
■
In conclusion, we have developed a novel route for the
synthesis of xyloketal natural products, namely xyloketal D,
xyloketal G, and the related natural product alboatrin, based on
gold-catalyzed xyloketalization in the key step. Notably, our
approach is adaptable to chiral synthesis of these targets if the
known chiral lactone, that is (R)-20,6b,c,21 is employed in the
initial condensation steps.
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calcd 191.1067, found 191.1064; TLC Rf 0.32 (20% EtOAc/petroleum
ether) (UV, I2).
EXPERIMENTAL SECTION
■
3-[2-(tert-Butyldimethylsilanyloxy)benzyl]dihydrofuran-2-
one (11). To a stirred solution of LDA (4.8 mmol, 1.2 equiv)
(prepared from diisopropylamine (1.3 mL, 9.6 mmol) and nBuLi (1.5
M in hexane, 3.2 mL, 4.8 mmol)) in THF (30 mL) was added a
solution of γ-butyrolactone (413 mg, 4.8 mmol) in 5 mL of THF at
−78 °C. After 20 min of stirring at that temperature, a solution of
benzyl bromide 10 (1.20 g, 4 mmol) in 5 mL of THF was added
dropwise over 10 min, and stirring was continued at −78 °C for 2 h.
After completion (TLC), the reaction was quenched with saturated aq
NH4Cl solution, extracted with diethyl ether (2 × 30 mL), dried over
anhyd Na2SO4, filtered, and evaporated. Purification by column
chromatography on silica gel gave the α-benzyl lactone 11(1.01 g,
82%) as a colorless liquid: IR (neat) 1774 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.15−7.10 (m, 2H), 6.89 (t, 1H, J = 7.4 Hz), 6.81 (d, 1H, J
= 8.0 Hz), 4.26 (dt, 1H, J = 7.0 Hz, J = 3.0 Hz), 4.16−4.12 (m, 1H),
3.32 (dd, 1H, J = 13.4 Hz, J = 4.0 Hz), 2.92 (m, 1H), 2.61 (dd, J = 13.6
Hz, J = 10.0 Hz), 2.16 (m, 1H), 1.99 (m, 1H), 1.01 (s, 9H), 0.25 (s,
3H), 0.24 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 179.1, 154.0, 131.0,
129.4, 128.0, 121.5, 118.9, 66.7, 40.0, 31.3, 28.4, 26.0, 18.5, −3.8, −4.0;
HRMS (CI MS) m/z for C17H27O3Si (M + H)+ calcd 307.1724, found
307.1695; TLC Rf 0.30 (10% EtOAc/petroleum ether) (UV, I2).
3-[2-(tert-Butyldimethylsilanyloxy)benzyl]pent-4-yn-1-ol
(12). To the α-benzyl lactone 11 (918 mg, 3 mmol) in toluene (30
mL) at −78 °C was added DIBAL-H (1 M in toluene, 3.6 mL, 3.6
mmol, 1.20 equiv) dropwise over 45 min. After being stirred at −78 °C
for 30 min (TLC shows consumption of starting material), the
reaction was quenched by the addition of methanol (1 mL) at −78 °C.
Saturated aq NH4Cl solution was added, and the reaction was allowed
to warm to room temperature. The layers were separated, and the
aqueous layer was extracted with ethyl acetate (3 × 20 mL). The
combined organic extracts were washed with brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting clear oil was
directly subjected to the next reaction step. LDA (10.5 mmol, 3.5
equiv) was freshly prepared from diisopropylamine (3 mL, 21 mmol, 7
equiv) and nBuLi (1.5 M in hexane, 7 mL, 10.5 mmol, 3.5 equiv) in
THF (28 mL) at −78 °C. After 20 min of stirring, TMSCHN2 (2 M in
Et2O, 3 mL, 6 mol, 2 equiv) was added dropwise over 1 h at −78 °C.
After being stirred at −78 °C for 30 min, the solution of the crude
lactol in THF (7 mL) was added dropwise over 20 min. The reaction
was warmed slowly to 0 °C over 5 h. After completion (TLC) of the
reaction, it was recooled to −78 °C and quenched with saturated aq
NH4Cl solution. The reaction mixture was allowed to warm to room
temperature. The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic
extracts were washed with brine (50 mL), dried (anhyd Na2SO4), and
concentrated in vacuo. The crude product was purified by flash
column chromatography (PET/AcOEt 20:1−15:1) to yield alkyne 12
9a-Methyl-3,3a,4,9a-tetrahydro-2H-furo[2,3-b]chromene (9).
TBAF (1 M in THF, 1.1 mL, 1.1 mmol), PPTS (301 mg, 1.2 mmol),
and AuCl (7 mg, 0.03 mmol) were added to a stirred solution of
alcohol 12 (304 mg, 1 mmol) in methanol (6 mL) under argon
atmosphere. After the reaction mixture had been stirred for 1 h, the
solvent was removed and the residue purified by flash chromatography
on silica gel (hexane/ethyl acetate, 3:1 v/v) to give 9 (182 mg, 96%) as
a white solid: mp 48−50 °C (lit.6i mp 44−47 °C); H NMR (400
1
MHz, CDCl3) δ 7.14−7.06 (m, 2H), 6.88−6.82 (m, 2H), 4.02−3.97
(m, 1H), 3.96−3.90 (m, 1H), 3.06 (dd, 1H, J = 16.6 Hz, J = 5.8 Hz),
2.80 (d, 1H, J = 16.0 Hz), 2.50−2.43 (m, 1H), 2.08−2.01 (m, 1H),
1.81−1.73(m, 1H), 1.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
153.9, 129.5, 127.9, 120.9, 119.6, 117.2, 107.5, 67.0, 41.2, 29.0, 26.5,
23.4; HRMS (CI MS) m/z for C12H15O2 (M + H)+ calcd 191.1067,
found 191.1053; TLC Rf 0.72 (20% EtOAc/petroleum ether) (UV, I2).
2,4-Bis(tert-butyldimethylsilanyloxy)-6-methylbenzalde-
hyde (14). A mixture of orcinol-2-carboxaldehyde (900 mg, 5.9
mmol), imidazole (2.4 g, 35.5 mmol), and TBSCl (4.5 g, 29.6 mmol)
in anhydrous DMF (6.0 mL) was stirred at rt for about 24 h under N2
atmosphere. The mixture was then diluted with ethyl acetate (100 mL)
and H2O (30 mL). The organic layer was separated, washed with H2O
(4 × 30 mL) and brine, dried over anhyd Na2SO4, filtered, and
concentrated. The crude product was purified by silica gel column
chromatography (petroleum ether/ethyl acetate = 50:1) to give 14
1
(2.0 g, 89%) as a colorless oil: H NMR (200 MHz, CDCl3) δ 10.47
(s, 1H), 6.29 (s, 1H), 6.17 (d, 1H, J = 2.2 Hz), 2.52 (s, 3H), 1.00 (s,
9H), 0.97 (s, 9H), 0.26 (s, 6H), 0.23 (s, 6H); 13C NMR (50 MHz,
CDCl3) δ 191.2, 162.3, 161.1, 144.4, 120.3, 117.2, 108.7, 25.9, 25.7,
22.2, 18.5, 18.4, −4.1, −4.1; HRMS (CI MS) m/z for C20H37O3Si2 (M
+ H)+ calcd 381.2276, found 381.2271; TLC Rf 0.64 (5% EtOAc/
petroleum ether), (UV, I2).
3-[(2,4-Dimethoxy-6-methylphenyl)hydroxymethyl]-
dihydrofuran-2-one (16). A mixture of aldehyde 15 (1.8 g, 10
mmol) and γ-butyrolactone (1.29 g, 15 mmol) in THF (15 mL) was
added to a THF (30 mL) solution of LDA (15 mmol) prepared from
10 mL of nBuLi (1.5 M) and iPr2NH (4.2 mL, 30 mmol) at −78 °C.
The reaction mixture was warmed to 0 °C over a period of 7 h. After
completion, the reaction was quenched with saturated aq NH4Cl and
extracted with ethyl acetate. The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure, and the
residue on chromatographic purification (silica gel) gave 2.42 g of
1
product 16 as a white solid in 91% yield: mp 94−96 °C; H NMR
(200 MHz, CDCl3) δ 6.33 (s, 2H), 5.27−5.20 (m, 1H), 4.34 (dt, 1H, J
= 8.5 Hz, J = 3.2 Hz), 4.19 (q, 1H, J = 16.1 Hz), 4.08 (d, 1H, J = 5.2
Hz), 3.82 (s, 3H), 3.79 (s, 3H), 3.42 (q, 1H, J = 18.8 Hz), 2.41 (s,
3H), 2.09−1.80 (m, 2H); 13C NMR (50 MHz, CDCl3) δ 179.7, 159.8,
159.0, 138.8, 118.4, 107.9, 96.8, 68.6, 66.8, 55.5, 55.1, 44.1, 26.1, 20.6;
HRMS (ESI-TOF) m/z for C14H18NaO5 (M + Na)+ calcd 289.1046,
found 289.1045; TLC Rf 0.28 (20% EtOAc/petroleum ether) (UV, I2).
3-(2, 4-Dimethoxy-6-methylbenzyl)dihydrofuran-2-one (17).
To a solution of the aldol product 16 (2.4 g, 9.0 mmol) and Et3SiH
(4.3 mL, 27 mmol) in CH2Cl2 (50 mL) was added BF3·OEt2 (1.3 mL,
10 mmol) at 0 °C. After the reaction mixture was stirred at 0 °C for 2
h, saturated aqueous NaHCO3 solution was added. The organic
solution was separated, washed with brine, and dried (anhyd Na2SO4).
The solvent was concentrated, and then the residue was subjected to
silica gel column chromatography to give the benzyl lactone 17 (2.16
1
(712 mg, 78%) as a colorless oil: H NMR (200 MHz, CDCl3) δ
7.22−7.04 (m, 2H), 6.89−6.74 (m, 2H), 3.78 (t, 2H, J = 6.3 Hz), 2.78
(m, 2H), 2.06 (s, 1H), 1.81−1.56 (m, 2H), 0.99 (s, 9H), 0.21 (s, 6H);
13C NMR (50 MHz, CDCl3) δ 154.0, 131.7, 130.0, 127.6, 120.9, 118.4,
87.2, 70.2, 60.6, 37.5, 36.8, 28.5, 26.1, 18.4, −0.3, −3.9; HRMS (ESI-
TOF) m/z for C18H28NaO2Si (M + Na)+ calcd 327.1751, found
327.1749; TLC Rf 0.8 (10% EtOAc/petroleum ether) (UV, I2).
2-[2-(2-Hydroxyethyl)but-3-ynyl]phenol (8). TBAF·3H2O
(694 mg, 2.2 mmol) was added to a THF (20 mL) solution of 12
(609 mg, 2 mmol) at room temperature, and stirring was continued
for 1 h. After complete conversion (TLC), it was quenched by
addition of saturated aq NH4Cl solution. The layers were separated,
and the aqueous layer was extracted with ethyl acetate (3 × 20 mL).
The combined organic extracts were washed with brine (50 mL), dried
(anhyd Na2SO4), and concentrated in vacuo. The crude product was
purified by flash column chromatography on silica gel to give 8 (372
1
g, 96%) as a white solid: mp 86−88 °C; IR (neat) 1763 cm−1; H
NMR (200 MHz, CDCl3) δ 6.32 (s, 2H), 4.31 (dt, 1H, J = 8.35 Hz, J =
3.8 Hz), 4.11 (q, 1H, J = 15.7 Hz), 3.77 (s, 6H), 3.08 (q, 1H, J = 18.7
Hz), 2.82−2.76 (m, 2H), 2.30 (s, 3H), 2.19−1.94 (m, 2H); 13C NMR
(50 MHz, CDCl3) δ 179.6, 158.9, 158.7, 138.3, 118.1, 106.8, 96.1,
66.8, 55.4, 55.3, 39.6, 28.5, 26.1, 20.2; HRMS (ESI-TOF) m/z for
C14H19O4 (M + H)+ calcd 251.1278, found 251.1277; TLC Rf 0.40
(20% EtOAc/petroleum ether) (UV, I2).
1
mg, 98%) as a colorless liquid: H NMR (200 MHz, CDCl3) δ 7.17−
7.07 (m, 2H), 6.90−6.77 (m, 2H), 3.99−3.72 (m, 2H), 2.98−2.73 (m,
3H), 2.14 (d, 1H, J = 1.4 Hz), 1.79−1.69 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 154.3, 131.7, 128.2, 125.7, 120.7, 116.2, 87.2, 70.9,
61.1, 35.8, 35.8, 29.6; HRMS (CI MS) m/z for C12H15O2 (M + H)+
3-[2,4-Bis(tert-butyldimethylsilanyloxy)-6-methylbenzyl]-
dihydrofuran-2-one (18). BBr3 (1 M solution in DCM) (32 mL, 32
mmol) was added dropwise to a precooled solution of 17 (2 g, 8
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Article
mmol) at 0 °C in 100 mL of DCM. After being stirred at 0 °C for 1 h,
the solution was warmed to room temperature and stirring was
continued for 24 h at that temperature. On completion, the reaction
mixture was poured into water, and dil HCl (10%, 50 mL) was added.
The mixture was extracted with DCM; the organic layer was washed
with water, dried over anhydrous Na2SO4, and evaporated. The residue
thus obtained was used for the next step without purification
A mixture of residue, imidazole (3.25 g, 48 mmol), and TBSCl (6.1
g, 40 mmol) in anhydrous DMF (30 mL) was stirred at rt for about 24
h under N2 atmosphere. The mixture was then diluted with ethyl
acetate (200 mL) and H2O (100 mL). The organic layer was
separated, washed with H2O (4 × 50 mL) and brine, dried over anhyd
Na2SO4, filtered, and concentrated. The crude product was purified by
silica gel column chromatography (hexane/ethyl acetate = 50:2) to
give 18 (2.81 g, 78%) as a low-melting solid: mp 68−70 °C; IR (neat)
1774 cm−1; 1H NMR (200 MHz, CDCl3) δ 6.31 (d, 1H, J = 2.0 Hz),
6.20 (d, 1H, J = 2.0 Hz), 4.31 (dt, 1H, J = 8.3 Hz, J = 3.8 Hz), 4.11(q,
1H, J = 16.8 Hz), 3.09 (d, 1H, J = 10.3 Hz), 2.87−2.68 (m, 2H), 2.25
(s, 3H), 2.14−2.03 (m, 1H), 0.99 (s, 9H), 0.97 (s, 9H), 0.24 (s, 3H),
0.23(s, 3H), 0.18 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 179.3, 154.7,
154.3, 138.5, 121.2, 115.5, 108.7, 66.8, 39.7, 28.5, 26.8, 26.1, 25.8, 20.4,
18.5, 18.4, −3.8, −3.9; HRMS (ESI-TOF) m/z for C24H42NaO4Si2 (M
+ Na)+ calcd 473.2514, found 473.2519; TLC Rf 0.56 (10% EtOAc/
petroleum ether) (UV, I2).
HRMS (CI MS) m/z for C13H17O3 (M + H)+ calcd 221.1172, found
221.1169; TLC Rf 0.42 (20% EtOAc/petroleum ether) (UV, I2).
3-[(2,4-Dimethoxy-6-methylphenyl)hydroxymethyl]-4-
methyldihydrofuran-2-one (21). Aldol product 21 was prepared
from aldehyde 15 (1.8 g, 10 mmol) and lactone 20 (1.5 g, 15 mmol)
in 89% yield exactly following the procedure described for the
1
preparation of 16: mp 98−100 °C; H NMR (200 MHz, CDCl3) δ
6.27 (s, 2H), 5.19 (d, 1H, J = 9.6 Hz), 4.30 (t, 1H, J = 8.4 Hz), 4.25-
4.06(m, 1H), 3.74 (s, 3H), 3.72 (s, 3H), 3.65−3.61 (m, 1H), 2.96 (t,
1H, J = 9.8 Hz), 2.35 (s, 3H), 2.28−2.05 (m, 1H), 0.56 (d, 3H, J = 6.6
Hz); 13C NMR (50 MHz, CDCl3) δ 180.4, 159.9, 159.3, 139.0, 118.1,
107.9, 96.7, 73.0, 68.3, 55.5, 55.2, 50.2, 33.7, 20.9, 16.3; HRMS (FAB-
TOF) m/z for C15H20O5 (M)+ calcd 280.1305, found 280.1314; TLC
Rf 0.34 (20% EtOAc/petroleum ether) (UV, I2).
3-(2,4-Dimethoxy-6-methylbenzyl)-4-methyldihydrofuran-
2-one (22). Reduction product 22 was prepared from 21 (2.8 g, 10
mmol) in 96% yield exactly following the procedure described for the
1
preparation of 17: mp 63−65 °C; IR (neat) 1777 cm−1; H NMR
(200 MHz, CDCl3) δ 6.30 (s, 2H), 4.30 (t, 1H, J = 7.9 Hz), 3.75 (s,
6H), 3.61 (t, 1H, J = 8.4 Hz), 3.06 (dd, 1H, J = 13.9 Hz, J = 4.7 Hz),
2.80 (dd, 1H, J = 13.8 Hz, J = 9.0 Hz), 2.44−2.34 (m, 2H), 2.29 (s,
3H), 0.74 (d, 3H, J = 5.8 Hz); 13C NMR (50 MHz, CDCl3) δ 179.4,
158.8, 158.6, 138.2, 117.6, 106.6, 95.9, 72.5, 55.2, 55.1, 46.0, 36.7, 25.9,
20.2, 16.7; HRMS (FAB-TOF) m/z for C15H21O4 (M + H)+ calcd
265.1434, found 265.1439; TLC Rf 0.46 (20% EtOAc/petroleum
ether) (UV, I2).
3-[2,4-Bis(tert-butyldimethylsilanyloxy)-6-methylbenzyl]-
pent-4-yn-1-ol (19). To the TBS ether 18 (1.35 g, 3 mmol) in
toluene (30 mL) at −78 °C was added DIBAL-H (1 M in toluene, 3.6
mL, 3.6 mmol, 1.20 equiv) dropwise over 45 min. After being stirred at
−78 °C for 30 min, the reaction was quenched by the addition of
methanol (2 mL) at −78 °C. Saturated aq NH4Cl solution was added,
and the reaction was allowed to warm to rt. The layers were separated,
and the aqueous layer was extracted with ethyl acetate (3 × 20 mL).
The combined organic extracts were washed with brine (50 mL), dried
(anhyd Na2SO4), and concentrated in vacuo. The resulting clear oil
was directly subjected to the next reaction step. LDA (10.5 mmol, 3.5
equiv) was freshly prepared from diisopropylamine (3 mL, 21 mmol, 7
equiv) and nBuLi (1.5 M in hexane, 7 mL, 10.5 mmol, 3.5 equiv) in
THF (28 mL) at −78 °C. After 20 min of stirring, TMSCHN2 (2 M in
Et2O, 3 mL, 6 mol, 2 equiv) was added dropwise over 1 h at −78 °C.
After being stirred at −78 °C for 30 min, the solution of the crude
lactol in THF (7 mL) was added dropwise over 20 min. The reaction
was warmed slowly to 0 °C over 5 h. After completion (TLC) of the
reaction, it was recooled to −78 °C and quenched with saturated aq
NH4Cl solution. The reaction mixture was allowed to warm to room
temperature. The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic
extracts were washed with brine (50 mL), dried (anhyd Na2SO4), and
concentrated in vacuo. The crude product was purified by flash
column chromatography (petroleum ether/AcOEt 20:1−15:1) to yield
3-[2,4-Bis(tert-butyldimethylsilanyloxy)-6-methylbenzyl]-4-
methyldihydrofuran-2-one (23). Compound 23 was prepared from
22 (2.38 g, 9 mmol) in 80% yield following the procedure described
1
for the preparation of 18: mp 123−125 °C; H NMR (200 MHz,
CDCl3) δ 6.31 (s, 1H), 6.20 (d, 1H, J = 2.2 Hz), 4.32 (t, 1H, J = 7.9
Hz), 3.62 (t, 1H, J = 8.9 Hz), 3.13 (dd, 1H, J = 13.9 Hz, J = 3.9 Hz),
2.80 (dd, 1H, J = 13.9 Hz, J = 10.4 Hz), 2.48−2.36 (m, 2H), 2.25 (s,
3H), 0.99 (s, 9H), 0.97 (s, 9H), 0.67(d, 3H, J = 6.0 Hz), 0.24 (s, 3H),
0.23 (s, 3H), 0.17 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 179.5,
154.7, 154.3, 138.5, 120.9, 115.5, 108.6, 72.7, 46.1, 36.9, 29.8, 26.8,
26.0, 25.8, 20.4, 18.4, 18.1, 16.8, −3.4, −3.9, −4.2; HRMS (CI MS) m/
z for C25H45O4Si2 (M + H)+ calcd 465.2851, found 465.2857; TLC Rf
0.74 (10% EtOAc/petroleum ether), (UV, I2).
3-[2,4-Bis(tert-butyldimethylsilanyloxy)-6-methylbenzyl]-2-
methylpent-4-yn-1-ol (24). To the TBS ether 23 (930 mg, 2 mmol)
in toluene (20 mL) at −78 °C was added DIBAL-H (1 M in toluene,
2.4 mL, 2.4 mmol, 1.20 equiv) dropwise over 45 min. After being
stirred at −78 °C for 30 min, the reaction was quenched by the
addition of methanol (1 mL) at −78 °C. Saturated aq NH4Cl solution
was added, and the reaction was allowed to warm to room
temperature. The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic
extracts were washed with brine (50 mL), dried (anhyd Na2SO4), and
concentrated in vacuo. The resulting clear oil was directly subjected to
the next reaction step. LDA (20 mmol, 10 equiv) was freshly prepared
from iPr2NH (4.2 mL, 30 mmol, 15 equiv) and nBuLi (1.5 M in
hexane, 13.3 mL, 20 mmol, 10 equiv) in THF (30 mL) at −78 °C.
After continued stirring at the same temperature for 20 min,
TMSCHN2 (2 M in Et2O, 10 mL, 20 mol, 10 equiv) was added
dropwise over 1 h and the reaction mixture stirred for 1 h. Then the
solution of crude lactol in THF (6 mL) was added dropwise over 20
min. The reaction was warmed slowly to room temperature over 1 h,
and then it was refluxed for 3 h. After completion (TLC) of the
reaction, it was recooled to −78 °C and quenched with saturated aq
NH4Cl solution. The reaction mixture was allowed to warm to room
temperature. The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 20 mL). The combined organic
extracts were washed with brine (50 mL), dried (anhyd Na2SO4), and
concentrated in vacuo. The crude product was purified by flash
column chromatography (petroleum ether/AcOEt 20:1−15:1) to yield
1
alkyne 19 (1. 09 g, 81%) as a colorless oil: H NMR (400 MHz,
CDCl3) δ 6.29 (s, 1H), 6.18 (s, 1H), 3.82−3.74 (m, 2H), 2.87−2.81
(m, 2H), 2.74−2.68 (m, 1H), 2.28 (s, 3H), 2.04(d, 1H, J = 1.2 Hz),
1.73−1.66 (m, 2H), 1.01 (s, 9H), 0.97 (s, 9H), 0.24 (s, 3H), 0.23 (s,
3H), 0.18 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 154.5, 153.9,
138.9, 121.3, 114.8, 107.9, 87.4, 70.0, 61.5, 36.8, 32.1, 29.6, 28.5, 25.8,
25.6, 20.5, 18.2, 18.1, −4.1, −4.1, −4.4; HRMS (CI MS) m/z for
C25H45O3Si2 (M + H)+ calcd 449.2902, found 449.2890; TLC Rf 0.52
(10% EtOAc/petroleum ether) (UV, I2).
Noralboatrin (13). TBAF (1 M in THF, 2.1 mL, 2.1 mmol), PPTS
(552 mg, 2.2 mmol), and AuCl3 (9 mg, 0.03 mmol) were added to a
stirred solution of alcohol 19 (450 mg, 1 mmol) in methanol (6 mL)
under argon atmosphere. After the reaction mixture had been stirred
for 1 h, the solvent was removed and the residue purified by flash
chromatography on silica gel to give noralboatrin 13 (205 mg, 93%) as
a white solid: mp 146−148 °C (lit.19 mp 148−149 °C); 1H NMR (400
MHz, CDCl3) δ 6.29 (s, 1H), 6.22 (s, 1H), 4.75 (brs, 1H), 4.03 (dt,
1H, J = 9.0 Hz, J = 2.8 Hz), 3.94 (q, 1H, J = 16.4 Hz), 2.73 (s, 2H),
2.50−2.42 (m, 1H), 2.17 (s, 3H), 2.10−2.01 (s, 1H), 1.85−1.74 (m,
1H), 1.52 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.9, 154.2,
138.5, 109.9, 109.8, 106.5, 101.8, 66.9, 40.9, 29.2, 23.3, 22.9, 19.5;
1
alkyne 24 (666 mg, 72%) as a colorless oil: H NMR (200 MHz,
CDCl3) δ 6.29 (s, 1H), 6.19 (s, 1H), 3.78−3.56 (m, 2H), 2.85−2.71
(m, 3H), 2.29 (s, 3H), 1.95 (s, 1H), 1.84−1.74 (m, 2H), 1.08 (d, 3H, J
= 6.8 Hz), 1.00 (s, 9H), 0.97 (s, 9H), 0.24(s, 6H), 0.18 (s, 6H); 13C
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1
NMR (50 MHz, CDCl3) δ 154.8, 154.1, 139.2, 122.0, 115.1, 108.3,
86.1, 71.0, 66.0, 39.3, 35.3, 29.9, 26.1, 25.9, 20.8, 18.5, 18.4, 16.3, 1.24,
−3.7, −4.1; HRMS (CI MS) m/z for C26H47O3Si2 (M + H)+ calcd
463.3058, found 463.3062; TLC Rf 0.64 (10% EtOAc/petroleum
ether) (UV, I2).
Alboatrin (4). Alboatrin (4) was prepared from 24 (600 mg, 1.3
mmol) in 92% yield following the procedure described for the
preparation of 13: mp 148−149 °C (lit.6f mp 148−149 °C); 1H NMR
(400 MHz, CDCl3) δ 6.29 (d, 1H, J = 2.0 Hz), 6.21(d, 1H, J = 2.4
Hz), 4.66 (brs, 1H), 4.18 (t, 1H, J = 8.2 Hz), 3.51 (t, 1H, J = 8.6 Hz),
2.70−2.68 (m, 2H), 2.19 (s, 3H), 2.15−2.09 (m, 1H), 1.93 (ddd, 1H, J
= 11.0 Hz, J = 5.5 Hz, J = 2.0 Hz), 1.50 (s, 3H), 1.06 (d, 3H, J = 6.4
Hz); 13C NMR (100 MHz, CDCl3) δ 154.7, 153.9, 138.4, 109.7, 109.6,
107.2, 101.7, 74.1, 48.2, 35.4, 22.9, 21.6, 19.5, 16.0; HRMS (CI MS)
m/z for C14H19O3 (M + H)+ calcd 235.1329, found 235.1333; TLC Rf
0.14 (10% EtOAc/petroleum ether) (UV, I2).
for the preparation of 13: mp 122−123 °C; H NMR (200 MHz,
CDCl3) δ 6.96 (t, 1H, J = 8.1 Hz), 6.44 (d, 1H, J = 8.0 Hz), 6.37 (d,
1H, J = 7.8 Hz), 5.53 (brs, 1H), 4.21 (t, 1H, J = 8.3 Hz), 3.54 (t, 1H, J
= 8.4 Hz), 2.90 (dd, 1H, J = 24.3 Hz, J = 1.4 Hz), 2.74 (dd, 1H, J =
17.5 Hz, J = 6.2 Hz), 2.24−2.06 (m, 1H), 2.00−1.90 (m, 1H), 1.53 (s,
3H), 1.07 (d, 3H, J = 6.6 Hz); 13C NMR (50 MHz, CDCl3) δ 154.6,
154.3, 127.7, 109.8, 107.4, 107.0, 106.4, 74.2, 47.7, 35.6, 23.0, 19.0,
16.1; HRMS (CI MS) m/z for C13H17O3 (M + H)+ calcd 221.1172,
found 221.1178; TLC Rf 0.44 (20% EtOAc/petroleum ether) (UV, I2).
Xyloketal D (2). To a solution containing 35 (220 mg, 1 mmol) in
7 mL of 1,2-dichloroethane at −10 °C was added 4 mL (4 mmol) of
TiCl4 (1.0 M in CH2Cl2). The reaction mixture was stirred for 5 min
at −10 °C, and 1.2 mL (120 mg, 1.5 mmol) of acetyl chloride solution
in DCE (from stock solution: 1.1 mL acetyl chloride dissolved in 10
mL DCE) was added. The reaction mixture was stirred at room
temperature for 24 h. Then the reaction mixture was poured into 50
mL of 2 N HCl (aq), filtered through a pad of Celite, and washed with
30 mL of ethyl acetate. The organic phase was separated, and the
aqueous phase was extracted with (3 × 10 mL) ethyl acetate. The
combined organic phase was dried (Na2SO4) and concentrated under
reduced pressure to afford a crude residue. The residue was purified by
flash chromatography on a silica gel column. Elution with 1:5 ethyl
acetate−hexanes gave 2 as a white solid: yield 214 mg (82%): mp 78−
3-[(2,6-Dimethoxyphenyl)hydroxymethyl]-4-methyldihy-
drofuran-2-one (27). Aldol product 27 was prepared from aldehyde
25 (1.66 g, 10 mmol) and lactone 20 (1.5 g, 15 mmol) in 90% yield
following the procedure described for the preparation of 16: mp 62−
1
63 °C; H NMR (200 MHz, CDCl3) δ 7.16 (t, 2H, J = 8.4 Hz), 6.49
(d, 4H, J = 8.4 Hz), 5.57−5.49 (m, 1H), 5.32(t, 1H, J = 7.9 Hz), 4.34−
4.22 (m, 2H), 3.76 (s, 12 H), 3.71−3.58 (m, 2H), 2.86(t, 1H, J = 8.3
Hz), 2.81−2.70 (m, 1H), 2.51(dd, 1H, J = 7.6 Hz, J = 5.4 Hz), 2.27−
2.13(m, 1H), 0.86 (d, 3H, J = 6.6 Hz), 0.68 (d, 3H, J = 6.6 Hz); 13C
NMR (50 MHz, CDCl3) δ 178.9, 177.0, 158.3, 157.6, 129.5, 129.1,
116.0, 116.0, 104.4, 104.3, 72.9, 72.7, 67.0, 66.4, 55.8, 55.7, 53.2, 51.3,
33.5, 31.6, 18.2, 17.0; HRMS (ESI-TOF) m/z for C14H18NaO5 (M +
Na)+ calcd 289.1046, found 289.1046; TLC Rf 0.48 (30% EtOAc/
petroleum ether) (UV, I2).
3-(2, 6-Dimethoxybenzyl)-4-methyldihydrofuran-2-one (29).
Reduction product 29 was prepared from 27 (2.4g, 9 mmol) in 98%
yield following the procedure described for the preparation of 17: mp
71−72 °C, IR (neat) 1771 cm−1; 1H NMR (200 MHz, CDCl3) δ 7.16
(t, 1H, J = 8.3 Hz), 6.53 (d, 2H, J = 8.4 Hz), 4.31 (dd, 1H, J = 8.7 Hz, J
= 7.6 Hz), 3.80 (s, 6H), 3.63 (t, 1H, J = 8.5 Hz), 3.17 (dd, 1H, J = 13.2
Hz, J = 5.0 Hz), 2.92 (dd, 1H, J = 13.2 Hz, J = 10 Hz), 2.59−2.43 (m,
1H), 2.40−2.27 (m, 1H), 0.71 (d, 3H, J = 6.4 Hz); 13C NMR (50
MHz, CDCl3) δ 179.8, 158.6, 127.8, 115.0, 103.7, 72.8, 55.7, 45.8,
36.3, 23.3, 17.2; HRMS (CI MS) m/z for C14H19O4 (M + H)+ calcd
251.1278, found 251.1281; TLC Rf 0.72 (20% EtOAc/petroleum
ether), (UV, I2).
79 °C (lit.6b mp 82 °C); H NMR (400 MHz, CDCl3) δ 13.12 (s,
1
1H), 7.52 (d, 1H, J = 9.2 Hz), 6.37 (d, 1H, J = 8.8 Hz), 4.21 (t, 1H, J =
8.4 Hz), 3.57 (t, 1H, J = 8.6 Hz), 2.96 (d, 1H, J = 18.0 Hz), 2.72 (dd,
1H, J = 17.8 Hz, J = 6.0 Hz), 2.55 (s, 3H), 2.10−1.96 (m, 2H), 1.53 (s,
3H), 1.08 (d, 3H, J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 203.0,
163.1, 159.7, 130.2, 113.3, 109.0, 108.5, 106.3, 74.5, 47.1, 35.3, 26.4,
22.9, 18.2, 16.0; HRMS (ESI-TOF) m/z for C15H18NaO4 (M + Na)+
calcd 285.1097, found 285.1102; TLC Rf 0.28 (20% EtOAc/petroleum
ether) (UV, I2).
3-[(2,4-Dimethoxyphenyl)hydroxymethyl]-4-methyldihy-
drofuran-2-one (28). Aldol product 28 was prepared from aldehyde
26 (1.66 g, 10 mmol) and lactone 20 (1.5 g, 15 mmol) in 93% yield
following the procedure described for the preparation of 16: 1H NMR
(200 MHz, CDCl3) δ 7.39 (t, 2H, J = 8.1 Hz), 6.54−6.45 (m, 4H),
5.53 (brs, 1H), 5.16 (d, 1H, J = 8.2 Hz), 4.35 (t, 2H, J = 7.9 Hz), 3.81
(s, 12H), 3.68 (dt, 2H, J = 8.8 Hz, J = 3.4 Hz), 2.82−2.50 (m, 4H),
0.67 (d, 3H, J = 6.4 Hz), 0.65 (d, 3H, J = 6.2 Hz); 13C NMR (50 MHz,
CDCl3) δ 179.1, 178.5, 160.1, 159.8, 157.0, 156.1, 128.3, 126.6, 121.9,
121.1, 104.2, 103.6, 97.7, 97.6, 72.9, 72.8, 67.6, 65.7, 54.9, 54.9, 52.4,
51.6, 33.0, 29.2, 20.5, 17.4, 16.2, 13.8; HRMS (ESI-TOF) m/z for
C14H18NaO5 (M + Na)+ calcd 289.1046, found 289.1044; TLC Rf 0.22
(20% EtOAc/petroleum ether), (UV, I2).
3-[2,6-Bis(tert-butyldimethylsilanyloxy)benzyl]-4-methyldi-
hydrofuran-2-one (31). Compound 31 was prepared from 29 (2.0g,
8 mmol) in 76% yield following the procedure described for the
1
3-(2,4-Dimethoxybenzyl)-4-methyldihydrofuran-2-one (30).
Reduction product 30 was prepared from 28 (2.4 g, 9 mmol) in 96%
yield following the procedure described for the preparation of 17: mp
preparation of 18: mp 111−112 °C; H NMR (200 MHz, CDCl3) δ
6.95 (t, 1H, J = 8.2 Hz), 6.46 (d, 2H, J = 8.2 Hz), 4.32 (t, 1H, J = 8.1
Hz), 3.62 (t, 1H, J = 8.7 Hz), 3.17 (dd, 1H, J = 13.2 Hz, J = 4.0 Hz),
2.88 (dd, 1H, J = 11.9 Hz, J = 10.6 Hz), 2.58 (ddd, 1H, J = 10.1 Hz, J =
9.7 Hz, J = 4.2 Hz), 2.50−2.39 (m, 1H), 1.01 (s, 18H), 0.68 (d, 3H, J
= 6.2 Hz), 0.26 (s, 6H), 0.24 (s, 6H); 13C NMR (50 MHz, CDCl3) δ
179.4, 155.3, 127.0, 120.4, 111.8, 72.7, 45.7, 36.8, 26.1, 25.9, 25.1, 18.5,
17.1, −3.9; HRMS (CI MS) m/z for C24H43O4Si2 (M + H)+ calcd
451.2694, found 451.2697; TLC Rf 0.44 (5% EtOAc/petroleum ether)
(UV, I2).
1
92−93 °C; H NMR (200 MHz, CDCl3) δ 7.05 (d, 1H, J = 7.8 Hz),
6.39(s, 1H), 6.37 (d, 1H, J = 7.6 Hz), 4.21(t, 1H, J = 8.2 Hz), 3.75 (s,
3H), 3.73 (s, 3H), 3.59 (t, 1H, J = 9.0 Hz), 3.15 (dd, 1H, J = 13.7 Hz, J
= 5.2 Hz), 2.82−2.60 (m, 1H), 2.49−2.38 (m, 1H), 2.28−2.12 (m,
1H), 0.82 (dd, 3H, J = 6.4 Hz, J = 0.8 Hz); 13C NMR (50 MHz,
CDCl3) δ 179.3, 159.8, 158.4, 131.3, 118.8, 104.0, 98.2, 72.5, 55.2,
55.1, 46.8, 35.7, 29.0, 16.5; HRMS (ESI-TOF) m/z for C14H18NaO4
(M + Na)+ calcd 273.1097, found 273.1096; TLC Rf 0.44 (20%
EtOAc/petroleum ether) (UV, I2).
3-[2,6-Bis(tert-butyldimethylsilanyloxy)benzyl]-2-methyl-
pent-4-yn-1-ol (33). Compound 33 (colorless liquid) was prepared
from 31 (1.35 g, 3 mmol) in 70% yield following the procedure
3-[2,4-Bis(tert-butyldimethylsilanyloxy)benzyl]-4-methyldi-
hydrofuran-2-one (32). Compound 32 was prepared from 30 (2.0 g,
8 mmol) in 79% yield following the procedure described for the
preparation of 18: mp 70−72 °C; 1H NMR (200 MHz, CDCl3) δ 6.96
(d, 1H, J = 8.2 Hz), 6.38 (dd, 1H, J = 7.8 Hz, J = 2.4 Hz), 6.31 (d, 1H,
J = 2.4 Hz), 4.23 (t, 1H, J = 8.3 Hz), 3.61 (t, 1H, J = 9.0 Hz), 3.34−
3.21 (m, 1H), 2.60−2.41 (m, 2H), 2.35−2.23 (m, 1H), 0.98 (s, 9H),
0.94 (s, 9H), 0.71 (d, 3H, J = 6.6 Hz), 0.22 (s, 6H), 0.15 (s, 6H); 13C
NMR (50 MHz, CDCl3) δ 179.3, 155.2, 154.5, 131.2, 121.9, 113.3,
111.0, 72.7, 46.8, 36.2, 30.5, 25.9, 25.8, 18.3, 18.1, 17.0, −3.5, −3.9,
−4.1, −4.3; HRMS (ESI-TOF) m/z for C24H42NaO4Si2 (M + Na)+
calcd 473.2514, found 473.2514; TLC Rf 0.48 (10% EtOAc/petroleum
ether), (UV, I2).
1
described for the preparation of 24: H NMR (200 MHz, CDCl3) δ
6.95−6.87 (m, 1H), 6.44−6.38 (m, 2H), 3.94−3.86 (m, 1H), 3.53−
3.41 (m, 1H), 3.09−2.88 (m, 2H), 2.67−2.59 (m, 1H), 1.80 (d, 1H, J
= 2.4 Hz), 1.80−1.62 (m, 1H), 1.07 (d, 3H, J = 6.8 Hz), 1.01 (s, 18H),
0.24 (s, 6H), 0.23 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 155.4,
126.6, 121.6, 111.4, 85.5, 70.2, 65.3, 39.5, 34.4, 27.6, 26.2, 18.5, 16.3,
1.25, 0.39, −0.25, −3.8, −3.9; HRMS (ESI-TOF) m/z for
C25H44NaO3Si2 (M + Na)+ calcd 471.2721, found 471.2722; TLC Rf
0.82 (10% EtOAc/petroleum ether) (UV, I2).
3,9a-Dimethyl-2,3,3a,9a-tetrahydro-4H-1,9-dioxacyclo-
penta[b]naphthalen-5-ol (35). Compound 35 was prepared from
33 (896 mg, 2 mmol) in 94% yield following the procedure described
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The Journal of Organic Chemistry
Article
3-[2,4-Bis(tert-butyldimethylsilanyloxy)benzyl]-2-methyl-
pent-4-yn-1-ol (34). Compound 34 was prepared from 32 (1.35 g, 3
mmol) in 73% yield following the procedure described for the
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preparation of 24: H NMR (200 MHz, CDCl3) δ 7.04 (dd, 1H, J =
8.2 Hz, J = 2.2 Hz), 6.39 (dd, 1H, J = 8.2 Hz, J = 2.4 Hz), 6.30 (t, 1H, J
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1.05−0.96 (21H), 0.24 (s, 6H), 0.18 (s, 6H); 13C NMR (50 MHz,
CDCl3) δ 154.8, 154.2, 131.5, 123.2, 112.5, 110.6, 85.7, 70.7, 65.1,
38.6, 35.6, 25.9, 25.7, 18.3, 16.1, 15.9, 14.3, −0.4, −4.0, −4.3; HRMS
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1
for the preparation of 13: mp 117−118 °C; H NMR (400 MHz,
CDCl3) δ 6.92 (d, 1H, J = 8.0 Hz), 6.42−6.38 (m, 2H), 5.37 (brs,
1H), 4.15 (t, 1H, J = 8.2 Hz), 3.49 (t, 1H, J = 8.4 Hz), 2.93 (dd, 1H, J
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was added. The reaction mixture was extracted with diethyl ether (10
mL × 3). The organic part was dried over anhyd Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/AcOEt 20:1−10:1) on a silica gel
column to yield 37 (181 mg, 86%) as a white solid: mp 67−68 °C; 1H
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2H), 4.15 (t, 1H, J = 8.3 Hz), 3.74 (s, 3H), 3.50 (t, 1H, J = 8.4 Hz),
2.95 (dd, 1H, J = 16.6 Hz, J = 5.8 Hz), 2.69 (d, 1H, J = 16.0 Hz),
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TLC Rf 0.82 (20% EtOAc/petroleum ether) (UV, I2).
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* Supporting Information
ORTEP diagram, crystallographic data, and CIF of compound
21, 1H and 13C NMR spectra of all unknown compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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■
Corresponding Author
*E-mail: tksr@chem.iitkgp.ernet.in.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by DST and CSIR, Government of
India. The NMR facility was supported by the FIST program of
the DST. We are thankful to Prof. T. Gallagher (Bristol, U.K.)
and Drs. S. Djuric and S. Cepa (Abbott, USA) for continued
help and support. T.K.S. is most thankful to Prof. R. V.
Venkateswaran for triggering our interest in xyloketal natural
products.
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